Heart failure is the leading cause of death, yet the peptidergic mechanisms involved in cardiac dysfunction are not completely understood (Jessup, M., and Brozena S. (2003)). Identifying small cardioregulatory peptides is significant because it can provide potential target molecules for drug development and therapeutic strategies to address cardiac dysfunction. Vertebrate FMRFamide-related peptides (FaRPs) are expressed in regions of the central nervous system involved in cardiac regulation (Fukusumi et al. (2001), Ukena et al. (2001), Yano et al. (2003)); however, relatively little is known about their function. The first RFamide-containing peptide discovered was the invertebrate tetrapeptide, FMRFamide (Price, D. A., and Greenberg, M. J. (1977)). The isolation of FMRFamide from clam ganglia as a cardioregulatory peptide led to the subsequent identification of structurally-related bio- and cardio-active peptides throughout the animal kingdom, in invertebrates and vertebrates (Fukusumi, S. et al. (2006), Nichols, R. (2003)).
The FaRP superfamily of FMRFamide-related peptides is subdivided into smaller groups based on the XRFamide motif, where X defines the subgroup. The invertebrate myosuppressin peptides belong to the LRFamide subgroup. The structure of Drosophila melanogaster myosuppressin, dromyosuppressin (DMS), is TDVDHVFLRFamide (SEQ ID NO: 1) (Nichols, R. (1992)). Myosuppressins have been extensively studied in invertebrates as myoinhibitory peptides that decrease heart rate and amplitude of ejection (Robb, S. et al. (1989), Robb, S., and Evans, P. (1994), Wasielewski, O., and Skonieczna, M. (2008), Stevens, J. S. et al. (2009), Angioy, A. M. et al. (2007)).
While the vast majority of FaRP-related cardiovascular research has been done in invertebrates, relatively little is known about the function of this cardioregulatory peptide family in mammals. However, mammalian RFamide-related peptide (RFRP) genes encode RFRP-1, which contains a C-terminal LRFamide (Hinuma, S. Et al. (2000), Liu, Q. Et al. (2001)). The structure of the human RFRP-1 (hRFRP-1) peptide is MPHSFANLPLRFamide (SEQ ID NO: 2) (Ubuka T. et al. (2009) PLoS One 4 (22): e8400; pages 1-7). An endogenous peptide with high structure identity to hRFRP-1 was isolated from bovine hypothalamus (Fukusumi, S. Et al. (2001)). Additionally, clusters of hRFRP-1 immunoreactive neurons and fibers are found in mammalian hypothalamus and nucleus of the solitary tract (NTS), an important site for integrative regulation of the cardiovascular system (Fukusumi, S. et al. (2001), Ukena, K., and Tsutsui, K. (2001), Yano, T. et al. (2003)).
U.S. Pat. Nos. 7,192,723 and 7,217,808 include disclosure of particular RFamide-related peptides for uses involving prolactin secretion and other therapeutic uses. WO 2007/045906, and WO 2004 026904 include disclosure of the particular RFamide-related peptides INSP207, INTP026, INTP027, and INTP028. U.S. Pat. No. 7,354,724 includes disclosure related to Drosophila melanogaster G protein coupled receptors. Particular cardiac effects of a non-vertebrate RFamide-related peptide hormone are discussed in Stevens J S et al. 2009, J Exp Biol: 212(Pt 24): 3961-76. Fang Q et al. (Eur J Pharmacol 2009 621: (1-3): 61-66) discuss cardiovascular effects of the RF amide-related peptide 26RFa.
As set forth in further detail below, methods and compositions directed to RFRP-1 polypeptides, are useful for modulating cardiac contractile function, for preventing and/or treating cardiac disorders; as well as tools for discovering agents that can modulate cardiac function, as tools for identifying the receptor of RFRP-1, and as tools for identifying diseases related to cardiac failure.